Prostate cancer is the second leading cause of cancer death in men. In 1992 the incidence of prostate cancer in the U.S. was 122,000 with 32,000 deaths. The lack of progress in prevention of this disease is hampered by inadequate experimental animal models. The purpose of this project is to develop and establish an efficient and reproducible animal model system for inducing prostate carcinogenesis, analyze the molecular and cellular events following the development of prostate cancer, and to identify agents that prevent and/or suppress prostate cancer incidence. We have induced prostate carcinogenesis by initiation with N-methyl- nitrosourea (NMU) and promotion with testosterone propionate (TP) in 3- month-old Lobund-Wistar rats. After 11-12 months post NMU/TP treatment, tumor incidence in the prostate and other accessory sex organs was approximately 70%. Treatment with tamoxifen, 4-HPR and deltanoid (Ro 24- 5531) decreased prostate tumor incidence. Kinetic study of the histological and pathological changes in animals 5-11 months following NMU/TP treatment allowed us to develop 3 categories and 6 stages of histologic scoring during prostate carcinogenesis. Molecular changes in the tumor show K-ras mutation of codon 12 (60%) and elevation of sulfated glycoprotein-2 (SGP-2) gene expression. We have succeeded in growing primary cultures of rat prostate epithelium in rats treated with NMU/TP for 7 months. We have immortalized 2 cell lines that are responsive to androgens and exogenous growth factors. Retinoic acid (1-1000 nanomolar) inhibits the growth of NRP-152 prostate cells and induces mRNA expression for TGF-beta1, -beta2 and -beta3. Antibodies to TGF-beta2 and monoclonal antibody that neutralizes all TGF-betas block retinoid growth inhibition, suggesting that growth inhibition by retinoids is mediated through induction of TGF-beta. Moreover, treatment of NRP-152 cells with TGF- beta under serum-free condition induces apoptosis or programmed cell death.